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Wnt3a Upregulates Brain-Derived Insulin by Increasing Neurod1 Via Lee et al. Molecular Brain (2016) 9:24 DOI 10.1186/s13041-016-0207-5 RESEARCH Open Access Wnt3a upregulates brain-derived insulin by increasing NeuroD1 via Wnt/β-catenin signaling in the hypothalamus Jaemeun Lee1, Kyungchan Kim1, Seong-Woon Yu1 and Eun-Kyoung Kim1,2* Abstract Background: Insulin plays diverse roles in the brain. Although insulin produced by pancreatic β-cells that crosses the blood–brain barrier is a major source of brain insulin, recent studies suggest that insulin is also produced locally within the brain. However, the mechanisms underlying the production of brain-derived insulin (BDI) are not yet known. Results: Here, we examined the effect of Wnt3a on BDI production in a hypothalamic cell line and hypothalamic tissue. In N39 hypothalamic cells, Wnt3a treatment significantly increased the expression of the Ins2 gene, which encodes the insulin isoform predominant in the mouse brain, by activating Wnt/β-catenin signaling. The concentration of insulin was higher in culture medium of Wnt3a-treated cells than in that of untreated cells. Interestingly, neurogenic differentiation 1 (NeuroD1), a target of Wnt/β-catenin signaling and one of transcription factors for insulin, was also induced by Wnt3a treatment in a time- and dose-dependent manner. In addition, the treatment of BIO, a GSK3 inhibitor, also increased the expression of Ins2 and NeuroD1. Knockdown of NeuroD1 by lentiviral shRNAs reduced the basal expression of Ins2 and suppressed Wnt3a-induced Ins2 expression. To confirm the Wnt3a-induced increase in Ins2 expression in vivo, Wnt3a was injected into the hypothalamus of mice. Wnt3a increased the expression of NeuroD1 and Ins2 in the hypothalamus in a manner similar to that observed in vitro. Conclusion: Taken together, these results suggest that BDI production is regulated by the Wnt/β-catenin/NeuroD1 pathway in the hypothalamus. Our findings will help to unravel the regulation of BDI production in the hypothalamus. Keywords: Brain-derived insulin, Hypothalamus, Wnt/β-catenin signaling, NeuroD1 Background Insulin produced in pancreatic β-cells is a major source Recognition of the importance of insulin action in the of plasma insulin. Insulin produced by the pancreas is brain has grown in many aspects such as energy balance, supplied to the brain from the blood circulation through glucose homeostasis, neuronal survival, synapse forma- the blood–brain barrier [11, 12], since insulin can be tion, and cognition [1–4]. In particular, studies on the transported across this barrier [13]. However, not all insu- relationship between metabolic and neurodegenerative lin in the brain comes from the pancreas, because insulin diseases emphasized the role of insulin signaling in the can also be produced in the brain [14, 15]. Insulin mRNA brain [5–10]. However, the source of insulin in the brain is detected in various regions of the brain both during has not been fully investigated. development and in adults. Rodents have two non-allelic insulin genes, Ins1 and Ins2 [14, 15]. In the pancreas, both genes are expressed, with Ins2 expressed at a higher level [16]. Interestingly, Ins1 mRNA is not detected in the * Correspondence: [email protected] 1Department of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of brain. Instead, Ins2 mRNA is found in limbic and olfactory Science and Technology (DGIST), 333 Techno Jungang-daero, regions, hippocampus, and hypothalamus [6, 17–22]. Hyeonpung-myeon, Dalseong-gun, Daegu 42988, South Korea Nevertheless, it is difficult to detect Ins2 mRNA in the 2Neurometabolomics Research Center, Daegu Gyeongbuk Institute of Science and Technology (DGIST), 333 Techno Jungang-daero, brain because of its quite low expression level. Using Hyeonpung-myeon, Dalseong-gun, Daegu 42988, South Korea single-cell digital PCR, one research group found that the © 2016 Lee et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Lee et al. Molecular Brain (2016) 9:24 Page 2 of 12 neurogliaform cells in the cerebral cortex express Ins2 underlying the regulation of BDI production in the mRNA [23]. To verify the production of insulin in the hypothalamus. brain, brain was stained with antibodies against connect- ing peptide (c-peptide), byproduct of proinsulin process- Results ing. C-peptide–positive signal was found in the central Wnt3a increases the levels of Ins2 mRNA and protein in nervous system, and the pattern of c-peptide staining N39 cells showed correlation with that of Ins2 expression [24, 25]. We used the immortalized mouse hypothalamic neuronal However, the mechanisms of local production of insulin cell line N39 (mHypoE-39) to investigate the mechanism in the brain, which is called brain-derived insulin (BDI), of BDI production, because N39 cells express Ins2 [14]. and its roles remain unclear. Consistent with the previous findings [14], Ins2 mRNA Wnt signaling is involved in brain development [26–28]. but not Ins1 mRNA was detected by quantitative real- Wnt proteins are a diverse family of secreted glycopro- time PCR (qRT-PCR) in N39 cells (data not shown). teins that act as ligands for receptor-mediated signaling Wnt3a increases insulin expression in pancreatic β-cells pathways [29]. The three well-characterized Wnt sig- and neuronal progenitor cells (derived from adult hippo- naling pathways are the canonical Wnt pathway, the campus or the olfactory bulb) via Wnt/β-catenin signaling non-canonical planar cell polarity pathway, and the [35, 47]. Therefore, we tested whether Wnt3a can induce non-canonical Wnt/calcium pathway. insulin production in N39 cells. The canonical Wnt signaling regulates the expression N39 cells were treated with Wnt3a (25 or 100 ng/mL) of insulin in pancreatic β-cells and the development of for 6, 12, or 24 h. After Wnt3a treatment for 6 h, the the pancreas [30–35]. Without Wnt ligands, β-catenin, Ins2 mRNA level increased significantly (by 4.1-fold at which enhances the expression of many genes in the nu- 25 ng/mL and 3.5-fold at 100 ng/mL Wnt3a; Fig. 1a), cleus, is degraded by the β-catenin destruction complex although this increase was not dose-dependent. After [36]. Glycogen synthase kinase 3 (GSK3), a key compo- 12 h, Wnt3a increased the Ins2 mRNA level by 3.9-fold nent of the β-catenin destruction complex, phosphory- at 25 ng/mL and 4.7-fold at 100 ng/mL. After 24 h, the lates β-catenin at Ser33, Ser37, and Thr41, leading to its Ins2 mRNA level was increased by 5.4-fold at 25 ng/mL degradation by the proteasome [37]. When Wnt ligands and 6.8-fold at 100 ng/mL of Wnt3a compared to vehicle- bind to Frizzled (Fz) receptor and its coreceptor, low treated cells. Thus, the Ins2 mRNA levels were significantly density lipoprotein receptor–related protein (LRP), the increased in Wnt3a-treated N39 cells in a time-dependent β-catenin destruction complex is disrupted by GSK3 manner at 12 and 24 h. inactivation [38]. Consequently, β-catenin accumulates in To confirm the expression of insulin, we checked its the cytosol and translocates into the nucleus to enhance protein level using immunofluorescence analysis with the expression of many target genes [39]. an antibody against proinsulin and found stronger The activity of the canonical Wnt signaling is also proinsulin-positive signals in N39 cells treated with observed in the adult mice hypothalamus [40, 41]. Wnt- Wnt3a (100 ng/mL) for 24 h than in vehicle-treated responsive cells are abundant in the paraventricular and cells (Fig. 1b). arcuate nuclei of the hypothalamus [42, 43]. In the mouse To further verify the production of insulin in Wnt3a- models of metabolic diseases such as diet-induced obese treated N39 cells, culture medium was collected after (DIO) mouse model and leptin-deficient (ob/ob) mouse Wnt3a treatment for 24 h, concentrated, and the concen- model, hypothalamic Wnt signaling is disrupted [44]. tration of immuno-reactive insulin was measured with GSK3 is increased in the hypothalamus of DIO mice, and ELISA. The concentration of insulin in culture medium a GSK3 inhibitor acutely improves glucose metabolism in was significantly increased (by 17.4 %) in cells treated with these mice [44]. In addition, the phosphorylated (active) Wnt3a (100 ng/mL) as compared to vehicle-treated cells form of LRP is down-regulated in ob/ob mice [45]. Down- (Fig. 1c). regulated Wnt signaling is reinstated by leptin treatment Taken together, our results indicate that Wnt3a in- [45]. These reports suggest that Wnt signaling is necessary creases the levels of insulin mRNA and protein in N39 for glucose homeostasis in the hypothalamus. However, cells. Furthermore, Wnt3a also increases secretion of the specific mechanism how Wnt signaling modulates me- insulin from N39 cells. tabolism in the hypothalamus has not yet been revealed. Insulin signaling plays many roles in the brain [46], Wnt3a induces insulin production in N39 cells through however, the mechanisms underlying the expression of the canonical Wnt/β-catenin signaling insulin in the brain have not been discovered yet. In this In the canonical Wnt signaling, Wnt ligands bind to study, we examined how Wnt signaling regulates the Fz receptor and LRP, and this binding results in the production of insulin in the hypothalamus. The results stabilization, accumulation, and nuclear translocation of our research will help to reveal the mechanisms of β-catenin [48, 49]. To determine whether Wnt3a Lee et al.
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